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It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3\u03b7 and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>The source of 14-3-3\u03b7 was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4<jats:sup>+<\/jats:sup> cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-\u03b1. Extracellular 14-3-3\u03b7 protein levels were examined by western blotting.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3\u03b7 protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-\u03b1, but not interleukin (IL) 6\/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-\u03b1-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3\u03b7 were detected in the culture supernatants of macrophages stimulated with diamide and TNF-\u03b1, but not IL-6\/sIL-6R.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Macrophages that highly express 14-3-3\u03b7 undergo TNF-\u03b1-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3\u03b7 into the extracellular space. The current study provides a novel mechanism for 14-3-3\u03b7 level increase in the RA synovial fluid.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13075-020-2110-9","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T14:02:47Z","timestamp":1581516167000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Tumour necrosis factor alpha promotes secretion of 14-3-3\u03b7 by inducing necroptosis in macrophages"],"prefix":"10.1186","volume":"22","author":[{"given":"Gulzhan","family":"Trimova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Yamagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Hirata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumi","family":"Uemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Satoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Biln","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Nakayamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter P.","family":"Maksymowych","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0807-7139","authenticated-orcid":false,"given":"Yoshiya","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"2110_CR1","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1016\/S0140-6736(17)31472-1","volume":"389","author":"IB McInnes","year":"2017","unstructured":"McInnes IB, Schett G. 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SN has received speaking fees from Bristol-Myers, UCB, Astellas, Abbvie, Eisai, Pfizer, and Takeda, and has received research grants from Mitsubishi-Tanabe, Novartis, and MSD. KY has received research grants from Mitsubishi-Tanabe. SH has received speaking fee and honoraria from AbbVie, Asahi-Kasei Pharma, Astellas, Ayumi, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Janssen, Kissei, Novartis, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, and UCB. NB is an employee of Augurex. All other authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}